A particular focus for our laboratory is a family of innate immune receptors known as Nod-like receptors (NLRs). Many of these have the capacity to form intracellular protein complexes called inflammasomes. These biological structures process the pro-inflammatory cytokines IL-1b and IL-18 into their mature forms. Our research has identified substances that activate the inflammasome, and mechanisms by which this inflammation causes disease.
Activation of the inflammasome also triggers an inflammatory form of cell death known as pyroptosis. This programmed form of cell death is a way by which an infected cell can prevent the spread of a micro-organism, but it can also contribute to inflammatory pathology during disease. We are researching the triggers and effectors for this new form of cell death.
This is a particularly exciting time to be working on inflammation because so many new drugs are coming to the clinic. We have the diverse research tools to determine where and why these new drugs can provide benefit.
Australia, The University of Melbourne, BSc (Hons), PhD
2017 HHMI-Wellcome International Research Scholar
2017 Viertel Fellowship
2014 Milstein Award, International Cytokine and Interferon Society
2013 International Society of Systemic Autoinflammatory Diseases, Young Investigator Award
2012 Innovation Fellow, VESKI
2018-20 Project Grant 1144282: PSTPIP1, Actin and the Pyrin inflammasome, NHMRC
2017-19 Millennium Award; Diabetes Australia Research Trust
2016-18 Project Grant 1099262: NLRP1 and IBD, NHMRC
2014-16 Project Grant 1057815: NLRP1 and Toxoplasma, NHMRC
2012 Establishment Grant, Ramaciotti Foundation
2017 Public Lecture: The Australian & New Zealand Association for the Advancement of Science
2013 VESKI schools symposium, talk to rural high school students (Victorian Endowment of Science Knowledge and Innovation)
2012 Tall Poppy Award winners discussion with secondary school students (Australian Institute of Policy and Science)
2012 The Melbourne School of Graduate Research workshop for start of career researchers, and considering careers in academia
Davidson S, Yu CH, Steiner A, Ebstein F, Baker PJ, Jarur-Chamy V, Hrovat Schaale K, Laohamonthonkul P, Kong K, Calleja DJ, Harapas CR, Balka KR, Mitchell J, Jackson JT, Geoghegan ND, Moghaddas F, Rogers KL, Mayer-Barber KD, De Jesus AA, De Nardo D, Kile BT, Sadler AJ, Poli MC, Krüger E, Goldbach Mansky R, Masters SL. Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24. Sci Immunol. 2022 Feb 11;7(68) PMID: 35148201
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Steiner A, Reygaerts T, Pontillo A, Ceccherini I, Moecking J, Moghaddas F, Davidson S, Caroli F, Grossi A, Castro FFM, Kalil J, Gohr FN, Schmidt FI, Bartok E, Zillinger T, Hartmann G, Geyer M, Gattorno M, Mendonça LO, Masters SL. Recessive NLRC4-Autoinflammatory Disease Reveals an Ulcerative Colitis Locus. J Clin Immunol. 2022 Feb;42(2):325-335. PMID: 34783940
Moecking J, Laohamonthonkul P, Chalker K, White MJ, Harapas CR, Yu CH, Davidson S, Hrovat-Schaale K, Hu D, Eng C, Huntsman S, Calleja DJ, Horvat JC, Hansbro PM, O’Donoghue RJJ, Ting JP, Burchard EG, Geyer M, Gerlic M, Masters SL. NLRP1 variant M1184V decreases inflammasome activation in the context of DPP9 inhibition and asthma severity. J Allergy Clin Immunol. 2021 Jun;147(6):2134-2145. PMID: 33378691
Yu CH, Davidson S, Harapas CR, Hilton JB, Mlodzianoski MJ, Laohamonthonkul P, Louis C, Low RRJ, Moecking J, De Nardo D, Balka KR, Calleja DJ, Moghaddas F, Ni E, McLean CA, Samson AL, Tyebji S, Tonkin CJ, Bye CR, Turner BJ, Pepin G, Gantier MP, Rogers KL, McArthur K, Crouch PJ, Masters SL. TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. Cell. 2020 Oct 29;183(3):636-649. PMID: 33031745
Tye H, Yu CH, Simms LA, de Zoete MR, Kim ML, Zakrzewski M, Penington JS, Harapas CR, Souza-Fonseca-Guimaraes F, Wockner LF, Preaudet A, Mielke LA, Wilcox SA, Ogura Y, Corr SC, Kanojia K, Kouremenos KA, De Souza DP, McConville MJ, Flavell RA, Gerlic M, Kile BT, Papenfuss AT, Putoczki TL, Radford-Smith GL, Masters SL. NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease. Nat Commun. 2018 Sep 13;9(1):3728. PMID: 30214011
Moghaddas F, Zeng P, Zhang Y, Schützle H, Brenner S, Hofmann SR, Berner R, Zhao Y, Lu B, Chen X, Zhang L, Cheng S, Winkler S, Lehmberg K, Canna SW, Czabotar PE, Wicks IP, De Nardo D, Hedrich CM, Zeng H, Masters SL. Autoinflammatory mutation in NLRC4 reveals a leucine-rich repeat (LRR)-LRR oligomerization interface. J Allergy Clin Immunol. 2018 Dec;142(6):1956-1967 PMID: 29778503
Murphy AJ, Kraakman MJ, Kammoun HL, Dragoljevic D, Lee MK, Lawlor KE, Wentworth JM, Vasanthakumar A, Gerlic M, Whitehead LW, DiRago L, Cengia L, Lane RM, Metcalf D, Vince JE, Harrison LC, Kallies A, Kile BT, Croker BA, Febbraio MA, Masters SL. IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome. Cell Metab. 2016 Jan 12;23(1):155-64. PMID: 26603191
Masters SL, Lagou V, Jeru I, Baker PJ, Van Eyck L, Parry DA, Lawless D, De Nardo D, Garcia-Perez JE, Dagley LF, Holley CL, Dooley J, Moghaddas F, Pasciuto E, Jeandel PY, Sciot R, Lyras D, Webb AI, Nicholson SE, De Somer L, van Nieuwenhove E, Ruuth-Praz J, Copin B, Cochet E, Medlej-Hashim M, Megarbane A, Schroder K, Savic S, Goris A, Amselem S, Wouters C, Liston A. Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Sci Transl Med. 2016 Mar 30;8(332):332ra45. PMID: 27030597
Kim ML, Chae JJ, Park YH, De Nardo D, Stirzaker RA, Ko HJ, Tye H, Cengia L, DiRago L, Metcalf D, Roberts AW, Kastner DL, Lew AM, Lyras D, Kile BT, Croker BA, Masters SL. Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1beta. J Exp Med. 2015 Jun 1;212(6):927-38. PMID: 26008898
Masters SL, Gerlic M, Metcalf D, Preston S, Pellegrini M, O’Donnell JA, McArthur K, Baldwin TM, Chevrier S, Nowell CJ, Cengia LH, Henley KJ, Collinge JE, Kastner DL, Feigenbaum L, Hilton DJ, Alexander WS, Kile BT, Croker BA. NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity. 2012 Dec 14;37(6):1009-23. PMID: 23219391
Genes of the innate immune system are activated by mutations in a number of hereditary periodic fever syndromes (autoinflammatory diseases). However in many cases the precise immune sensor that is triggered is not immediately clear.
We are particularly interested in innate immune sensors that drive autoinflammatory diseases associated with type I IFN (interferonopathies). These are frequently associated with the buildup of cytoplasmic DNA or RNA, triggering sensors such as cGAS and RigI/MDA5. We are now searching to see if these sensors are responsible for disease in particular inferferonopathies, and where they are not involved we are looking to identify novel sensors.
Project resource: Masters, S. (2019, February 3), Cytoplasmic innate immune sensors, The Biomedical & Life Sciences Collection, Henry Stewart Talks
Team member: Dr Sophia Davidson
Rapid advances in genetics are providing unprecedented insight into functions of the innate immune system, with identification of the mutations that cause monogenic autoinflammatory diseases. However, many patients do not have a mutation in one of the known disease causing genes, or have a novel mutation of unknown pathogenicity.
Therefore we have established an Australian Autoinflammatory Disease Registry (AADRY) with three main goals:
The organising committee for this registry includes clinicians from each of the major centres in Australia that treat patients with autoinflammatory disease. These organisations can enter details of their patients with autoinflammatory disease into an online database managed by the Masters laboratory at WEHI.
Clinicians will be able to search de-identified data to find resources, and network with others who have experience in the treatment of these rare conditions. Based on this registry, individuals and several families who tested negative for a mutation in known autoinflammatory disease genes have now been consented for exome sequencing, blood collected, DNA prepared and exomes sequenced.
Project resource: Cause of rare immune disease identified
Team member: Kelsey Breslin
Innate immune receptors can recognize foreign pathogens and alert the host to infection. More recently it has emerged that these same receptors can also recognise host molecules that are exposed as a result of cell stress or injury, as a surrogate marker of infection. However these same danger associated molecular patterns (DAMPs) can be present as a trigger for diseases such as allergy, autoimmunity and chronic inflammatory disease.
This project will uncover the roles of key innate immune receptors in laboratory models of these diseases, such as inflammatory bowel disease, type 2 diabetes and amyotrophic lateral sclerosis.
Team member: Shouya Feng